Orally Active Peptide Vector Allows Using Cannabis to Fight Pain While Avoiding Side Effects

The activation of cannabinoid CB₁ receptors (CB₁R) by Δ⁹-tetrahydrocannabinol (THC), the main component of Cannabis sativa, induces analgesia. CB₁R activation, however, also causes cognitive impairment via the serotonin 5HT_2A receptor (5HT_2AR), a component of a CB₁R–5HT_2AR heteromer, posing a serious drawback for cannabinoid therapeutic use. We have shown that peptides reproducing CB₁R transmembrane (TM) helices 5 and 6, fused to a cell-penetrating sequence (CPP), can alter the structure of the CB₁R–5HT_2AR heteromer and avert THC cognitive impairment while preserving analgesia. Here, we report the optimization of these prototypes into drug-like leads by (i) shortening the TM5, TM6, and CPP sequences, without losing the ability to disturb the CB₁R–5HT_2AR heteromer, and (ii) extensive sequence remodeling to achieve protease resistance and blood–brain barrier penetration. Our efforts have culminated in the identification of an ideal candidate for cannabis-based pain management, an orally active 16-residue peptide preserving THC-induced analgesia.